The availability and source of carbohydrate is the single most important environmental variable that affects the composition and pathogenic potential of supragingival dental plaque. Streptococcus mutans emerges as a significant constituent of cariogenic dental plaque as a direct result of repeated acidification of the oral biofilms through catabolism of exogenous carbohydrates. The persistence and virulence of S. mutans are inextricably intertwined with the genetic and physiologic responses of this organism to the source and availability of carbohydrates. S. mutans has the ability to catabolize a wide variety of sugars over a wide range of concentrations, to store carbohydrates in different forms for catabolism during nutrient limitation, and to adapt to the constant changes in carbohydrate source and availability in the oral cavity. Our studies focus in two general areas: one being a detailed analysis of regulation of the established virulence determinant fructan hydrolase (FruA), which continues to serve as an excellent model of gene regulation in S. mutans, and the other an investigation of two established regulators of carbohydrate utilization and their impact on global control of gene expression and regulation of documented virulence attributes of the organism, including fruA. This competing continuation builds on the foundation we established through studies of fruA, catabolite repression, and the role of CcpA and the sugarphosphotransferase system in regulation of gene expression. The Specific Aims for this proposal are: 1. Exploration of structure:function relationships in a unique four-component signal transduction system required for activation of fruA expression in response to inducer. 2. Dissecting the underlying mechanisms of CcpA-dependent and CcpA-independent carbohydrate catabolite repression in S. mutans.